Indan derivative and thromboxane antagonist containing the same

ABSTRACT

The present invention relates to indan derivatives represented by the formula (1) or pharmaceutically acceptable salts thereof: ##STR1## [wherein R 1  represents C1 to C12 alkyl, benzyl, styryl, naphthyl, optionally substituted phenyl or optionally substituted thienyl; R 2  represents carboxyl, C1 to C4 alkoxycarbonyl, ##STR2## Y represents --(CH 2 ) p  -- (wherein p represents an integer of 0 to 5), --CO--(CH 2 ) q  ˜, --CH(OH)--(CH 2 ) q  ˜, (wherein q represents an integer of 1 to 4, and the symbol ˜ represents a linkage to R 2 ), oxymethylene or ethylene; and n represents an integer of 1 to 4]. The compounds according to the present invention potently antagonize the action of thromboxane A 2 , and therefore useful for the treatment and prevention of diseases caused by thromboxane A 2  such as angiosis, vasospasm, asthma and the like.

TECHNICAL FIELD

The present invention relates to novel indan derivatives or saltsthereof which are capable of potently antagonizing the action ofthromboxane A₂ (hereinafter may be referred to as TXA₂) and aresignificant in the medical field. More particularly, the presentinvention relates to indan derivatives or salts thereof which are usefulfor the treatment and prevention of diseases or diseased states causedby TXA₂, such as thrombosis, vasospasm or asthma, and also tothromboxane antagonists containing the compounds.

BACKGROUND ART

TXA₂ is a metabolite of arachidonic acid widely found in organs ofcreatures, such as the liver, kidney, lung and the brain, and it isknown to have function of strongly coagulating the platelets andcontracting the blood vessel ("Cascade of Arachidonic Acid and Drug" byShozo YAMAMOTO, 1985).

Moreover, it is known that TXA₂ is associated with various diseases suchas cardiac infarction, angina pectoris, thrombosis, transient cerebralischemia, hemicrania, cerebral hemorrhage, cerebral infarction,arteriosclerosis, peripheral circulatory insufficiency or failure, highblood pressure, pulmonary embolism, bronchial asthma, bronchitis,pneumonia, nephritis, hepatitis, and shocks because it stronglycontracts the bronchi and the tracheal smooth muscles.

Accordingly, it is expected that effective treatments against theabove-mentioned diseases may be obtained by suppressing the action ofTXA₂, and many studies have already been reported. For example, Japanesepatent publication (Kokoku) 57-35910 discloses4-(2-phenylsulfonylaminoethyl)phenoxy acetic acid derivatives ascompounds which antagonize the action of TXA₂. These compounds, however,are not necessarily satisfactory in terms of the efficacy aspharmaceuticals, lasting ability of the action, adverse side effects andso on.

Under these circumstances, the present inventors have carried outcareful studies toward solving the above-mentioned problems, and havefound that certain indan derivatives or their salts have a muchstronger. TXA₂ antagonizing activity than the above-described4-(2-phenylsulfonylaminoethyl)phenoxy acetic acid derivatives, leadingto the completion of the invention.

DISCLOSURE OF THE INVENTION

According to the present invention, there are provided indan derivativesrepresented by the formula (1) or pharmaceutically acceptable saltsthereof: ##STR3## wherein R¹ represents C1 to C12 alkyl, benzyl, styryl,naphthyl, optionally substituted phenyl or optionally substitutedthienyl; R² represents carboxyl, C1 to C4 alkoxycarbonyl, ##STR4## Yrepresents --(CH₂)_(p) -- (wherein p represents an integer of 0 to 5),--CO--(CH₂)_(q) ˜, --CH(OH)--(CH₂)_(q) ˜, (wherein q represents aninteger of 1 to 4, and the symbol ˜ represents a linkage to R²),oxymethylene or ethylene; and n represents an integer of 1 to 4.

Moreover, the present invention provides thromboxane antagonistscontaining, as their active ingredients, the indan derivative of formula(1) above or pharmaceutically acceptable salts thereof.

The term "optionally substituted phenyl" means a phenyl groupsubstituted by C1 to C8 alkyl, C1 to C4 alkoxy, trifluoromethyl,trifluoromethoxy, nitro, amino, nitrile or by a halogen atom at one ortwo positions, or a phenyl group having no substituent. The term"optionally substituted thienyl" means a thienyl group substituted by C1to C4 alkyl, C1 to C4 alkoxy, phenylsulfonyl, trifluoromethyl or by ahalogen atom at one or two positions, or a thienyl group having nosubstituent.

BEST MODE FOR CARRYING OUT THE INVENTION

The indan derivatives (1) according to the present invention can beprepared as follows:

First, indan-2-ylalkylcarboxylic acid, which can be prepared by or basedon a known method, is converted to indan-2-ylalkylamine by a knownmethod such as a Curtius rearrangement of acylazide or the reduction ofcarboxylic amide, and is subsequently condensed with a sulfonating agentsuch as sulfonyl chloride to obtain a sulfonamide derivative representedby formula (2): ##STR5##

In the above and below-described formulae (1a), (1b), (1c), (1d), (1e),(1f), (2), (3), (4), (5), (6), (7), (8), (9), (10) and (11), the symbolY' represents --CO--(CH₂)_(q) ˜ (wherein q and ˜ individually have thesame meaning as defined before), and R¹, R² and n individually have thesame meaning as defined before.

Process A

The thus obtained sulfonamide derivative (2) is submitted to aFriedel-Crafts reaction in an inert solvent such as, and preferably,nitrobenzene, carbon disulfide, tetrachloroethane, dichloroethane ordichloromethane, in the presence of an acid chloride preferably acetylchloride and Lewis acid, and further preferably in the presence ofaluminum chloride, stannic chloride, zinc chloride or titaniumtetrachloride, in the temperature range of -10° to 50° C., and thereaction product (3) is converted to a compound (4) via a Bayer-Villigerreaction by the use of an organic peracid such as m-chloroperbenzoicacid and perbenzoic acid. The reaction scheme is shown below: ##STR6##

Subsequently, the ester bond of the compound (4) is hydrolyzed toconvert the compound (4) to compound (5) with an acid or alkali, and thecompound (5) is alkylated, on the position-selective basis, through areaction with a halide having a desired substituent, to produce thetarget compound (1a). ##STR7##

Process B

The methyl indan-2-alkane carboxylate (6) is converted to a compound (7)according to the Process A above, and then submitted to a Bayer-Villigerreaction. Subsequently, the phenol hydroxyl group is protected with asuitable protecting group such as aryl methyl and preferably benzyl,p-methoxybenzyl, 3,4-dimethoxybenzyl, and the ester (6) is hydrolyzedwith an acid or alkali. The free carboxylic acid is submitted to aCurtius rearrangement according to the Process A, and the obtainedcompound (8) is debenzylated to produce a compound (9) at roomtemperature under reducing conditions in a suitable solvent such asmethanol, ethanol, ethyl acetate and tetrahydrofuran, with the use of ametallic catalyst such as palladium, platinum, etc. Next, the phenolhydroxyl group is alkylated with a desired alkylating agent inaccordance with the method of Process A for eliminating the amino group,and thus the target compound (1a) is prepared from the obtained compound(10) by the method described above. The reaction scheme is shown below:##STR8##

Process C

The target compound (1b) below can be obtained by a known method("Organic Synthesis", John Willy and Sons, Collective Volume V, 8-11)starting from the compound (3). ##STR9##

Process D

The compound (2) is condensed with alpha-chloro-alphamethylthio ethylacetate ester according to a known method ("Chem. Pharm. Bull., 30,915-921) in the presence of a Lewis acid, and then submitted to thereductive desulfurization to obtain the target compound (1c) below. Ifdesired, the ester is hydrolyzed with an acid or an alkali.Alternatively, the compound (1c) can be obtained by first submitting theindan-2-alkyl carboxylic acid and alpha-chloro-alpha-methylthiosulfateto a Friedel-Crafts reaction, followed by converting the carboxyl groupto a sulfonyl amino group. ##STR10##

Process E

The target compound (1d) below can be obtained by conducting aFriedel-Crafts reaction using the compound (2) together with a desiredacid chloride or acid anhydride according to the Process A. ##STR11##

Process F

The aldehyde derivative (11) can be synthesized from the compound (2) bya known method (Chem. Ber., 93, 88 (1960)). The aldehyde derivative (11)can be converted to the target compound (1e) shown below by a knownreaction such as a Wittig reaction or a Knoevenagel reaction. Moreover,the target compound (1f) also shown below can be obtained by reducingthe double bond in compound (1e), if desired. The reaction scheme isshown below. ##STR12##

The present compounds (1) embraces two kinds of optical isomerscontributed to the asymmetric carbon atom present at the 2-position ofthe indan skeleton, and their mixture.

The present compound (1) is suited for the pharmaceutical use in theform of a free compound or of a salt of the compound. When the compoundis used as a medicine, salts should be pharmaceutically acceptable ones,and include inorganic salts such as sodium salts, potassium salts,calcium salts and magnesium salts, and organic salts such as ammoniumsalts, pyridine salts, triethylamine salts, ethanolamine salts and basicamino acid salts.

The thus obtained present compounds (1) have excellent TXA₂ antagonizingactivity as described hereinbelow and are very safe. Therefore, they areuseful as a platelet aggregation inhibitory agent and can be utilizedfor the prevention and treatment of various diseases caused by TXA₂,such as embolism and thrombosis, including cerebral thrombosis, coronarythrombosis, pulmonary embolism, chronic arterial obstruction,thromboangiitis and the like. The compounds (1) according to the presentinvention and their pharmaceutically acceptable salts are also usefulfor the treatment, alleveation and prevention of miocardial ischemia,angina pectoris, coronary contraction, cerebrovasucular contractionafter subarachnoidal hemorrhage, cerebral hemorrhage, asthma, and thelike.

The compounds (1) according to the present invention and theirpharmaceutically acceptable salts can be administered via oral ornon-oral route. For oral route administration, the present compounds canbe formed into solid preparations such as tablets, powder and capsulesby suitably combining proper additives including vehicles such aslactose, mannitol and corn starch; binders such as cellulosederivatives, gum arabic and gelatin; disintegrators such ascarboxymethylcellulose calcium; and lubricants such as talc andmagnesium stearate. Alternatively, the present compounds can be formedinto liquid preparations such as solutions, suspensions, emulsions andso on.

For non-oral administration, may be mentioned injection preparations,where the present compounds are combined with water, ethanol, glycerolor the like.

The amount of the compounds (1) according to the present invention ortheir pharmaceutically acceptable salts required for the treatment orthe prevention of a subject suffering from aforementioned diseasesdiffers depending on the physical form of the preparation,administration route, age or conditions of the disease. Generally, theamount via oral route administration for an adult is 1-1000 mg andpreferably 5-500 mg per day. It is preferred that the compounds beadministered as divided into two to three times a day.

EXAMPLES

The present invention will hereinafter be described in more detail byway of examples, which however, should not be construed as limiting theinvention thereto.

First, processes for preparing the intermediates for the presentcompounds (1) are described in the following Reference Examples 1-3.

Reference Example 1

Preparation of 2-[(4-chlorophenyl)sulfonylaminomethyl]indan:

The title compound was obtained via the following Steps 1 and 2.

Step 1

Preparation of 2-(benzyloxycarbonylaminomethyl)indan:

17.6 g (0.10 mol) of (indan-2-yl)acetic acid was dissolved in 150 ml oftoluene, to which were added 15.3 ml (0.11 mol) of triethylamine and33.0 g (0.12 mol) of diphenylphosphorylazide, and stirred at roomtemperature for 30 minutes. The mixture was added with 16.6 g (0.15 mol)of benzyl alcohol and refluxed for 18 hours. After cooling, the solventwas distilled under reduced pressure, and the residue was added with 500ml of ethyl acetate, washed with 1N sodium hydroxide, and condensed. Theresidue was purified by silica gel column chromatography (ethylacetate:hexane=1:3), and the crystals collected were recrystallized froma solvent mixture of ethyl acetate and hexane to obtain 24.3 g of2-(benzyloxycarbonylaminomethyl)indan as colorless needles. Yield: 86%

The melting point, IR and MS data are as follows:

Melting point: 87-89° C.

IR(KBr)cm⁻¹ : 3325, 1675, 1525

MS(m/z): 281 (M⁺)

Step 2

Preparation of 2-[(4-chlorophenyl)sulfonylaminomethyl]indan:

10.6 g (37.7 mmol) of 2-(benzyloxycarbonylaminomethyl)indan wasdissolved in 100 ml of methanol, to which 1.3 g of palladium on carbonwas added and stirred for 4 hours in the stream of hydrogen. Thecatalyst was removed by filtration, the solvent was evaporated, and 5.04g of 2-(aminomethyl)indan was obtained. The obtained compound wasimmediately dissolved in 150 ml of methylene chloride, to which 100 mlof water and 6.2 g of potassium carbonate were added, and the mixturewas vigorously stirred. 8.02 g (38.0 mmol) of 4-chlorobenzenesulfonylchloride was added thereto portionwise under ice-cooling, followed bystirring for 30 minutes. The organic phase was collected, dried and thesolvent was removed by distillation. The crystalline residue wasrecrystallized from a solvent mixture of ethyl acetate and hexane toobtain 9.82 g of 2-[(4-chlorophenyl)sulfonylaminomethyl]indan ascolorless needles. Yield: 76%

The melting point, IR and MS data are as follows:

Melting point: 134°-135° C.

IR(KBr)cm⁻¹ : 3250, 1315, 1150

MS(m/z): 321 (M⁺)

The chemical formula is as follows: ##STR13##

Reference Example 2

Preparation of 2-[3-(4-chlorophenyl)sulfonylaminopropyl]indan:

The above compound was obtained via the following Steps 1 to 5.

Step 1

Preparation of 2-(indan-2-yl)ethanol:

1.02 g (26.8 mmol) of lithium aluminum hydride was suspended in 100 mlof tetrahydrofuran, to which was added dropwise a solution of 10 mltetrafuran containing 5.06 g (26.6 mmol) of methyl(indan-2-yl)acetateunder ice-cooling. After completion of the addition, stirring wascontinued for 1 hour, during which 1 ml water, 1 ml of 15% sodiumhydroxide and 3 ml water were added dropwise in this order fordecomposing the excessive reducing agent. The solid matter was removedby filtration, the filtrate was condensed and the residue was purifiedby silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain4.30 g of a colorless oil. Yield: 100%

The IR and MS data are as follows:

IR(neat)cm⁻¹ : 3320, 2920, 1480, 1050

MS(m/z): 162 (M⁺)

Step 2

Preparation of (indan-2-yl)acetaldehyde:

18.5 g of pyridinium chloromate and 70 g of Celite (No. 545) weresuspended in 220 ml of methylene chloride, to which 15 ml solution ofmethylene chloride containing 4.30 g (26.6 mmol) of ethanol was addeddropwise under ice-cooling. Stirring was continued for 1 hour under theice-cooling condition, and then 2 hours at room temperature. Thereaction product was added with 250 ml ether for dilution, andsubsequently passed through 100 g of a layered silica gel for separatinginorganic matters. The solvent was distilled off to obtain 3.97 g of(indan-2-yl)acetaldehyde as a colorless oil. Yield: 93%

The IR and MS data are as follows:

IR(neat)cm⁻¹ : 1720, 1615, 1580

MS(m/z): 160 (M⁺)

Step 3

Preparation of benzyl-4-(indan-2-yl)-2-butenoate:

3.97 g (24.8 mmol) of (indan-2-yl)acetaldehyde was dissolved in 50 ml ofmethylene chloride, to which was added 12.2 g (29.8 mmol) ofbenzyloxycarbonylmethylene triphenyl phosphorane and stirred for 1.5hours. The solvent was distilled off and the residue was purified bysilica gel column chromatography (ethyl acetate:hexane=1:20) to obtain6.45 g colorless oil. Yield: 89%

The IR and MS data are as follows:

IR(neat)cm⁻¹ : 1715, 1650

MS(m/z): 292 (M⁺)

Step 4

Preparation of 4-(indan-2-yl)butanoic acid:

6.45 g (22.1 mmol) of benzyl-4-(indan-2-yl)-2-butenoate was dissolved in120 ml of methanol, to which 0.6 g of 10% palladium on carbon was addedand stirred vigorously for 2.5 hours in the stream of hydrogen. Thecatalyst was removed by filtration, the filtrate was condensed to obtain3.84 g of crystalline 4-(indan-2-yl)butanoic acid. Yield: 85%

The melting point and MS data are as follows:

Melting point: 75° C.

MS(m/z): 204 (M⁺)

Step 5

Preparation of 2-[3-(4-chlorophenyl)sulfonylaminopropyl]indan:

The title compound was synthesized in accordance with the procedure ofStep 2 of Reference Example 1, and recrystallized from a solvent mixtureof ethyl acetate and hexane. Yield: 68%

The melting point, IR and MS data are as follows:

Melting point: 103°-104° C.

IR(nujol)cm⁻¹ : 3250, 1615, 1575

MS(m/z): 349 (M⁺)

The chemical formula is as follows: ##STR14##

Reference Example 3

Preparation of 2-[2-(4-chlorophenyl)sulfonylaminoethyl]indan:

The title compound was obtained via the following Steps 1 to 3.

Step 1

Preparation of (indan-2-yl)acetamide:

35.3 g (0.20 mol) of (indan-2-yl)acetic acid was dissolved in 350 mlmethylene chloride, to which was added 26.5 g (0.22 mol) of thionylchloride and stirred for 4 hours at room temperature, followed byrefluxing for further 1.5 hours. After cooled and condensed underreduced pressure, the obtained oily residue was dissolved in 100 mlethyl acetate and added dropwise to 200 ml conc. aqueous ammonia whilestirred vigorously under ice-cooling. After stirring for 20 minutes, theprecipitates were collected by filtration and recrystallized from asolvent mixture of ethyl acetate and ethanol. 32.1 g of colorlesscrystal was obtained. Yield: 95%

The melting point, IR and MS data are as follows:

Melting point: 152°-154° C.

IR(KBr)cm⁻¹ : 3340, 3160, 1665, 1625

Ms(m/z): 175 (M⁺)

Step 2

Preparation of 2-(indan-2-yl)ethylamine:

8.77 g (0.23 mol) of lithium aluminum hydride was suspended in 400 ml oftetrahydrofuran, to which was added a suspension of 100 mltetrahydrofuran containing 27.8 g (0.160 mol) of (indan-2-yl)acetamideunder ice-cooling. The mixture was stirred for 30 minutes at roomtemperature, then refluxed for 5 hours. Under ice-cooling, 9 ml ofwater, 9 ml of 15% sodium hydroxide and 26 ml water were added theretodropwise in this order for decomposing the excessive reagent andseparating the solid matter. The filtrate was condensed to obtain 26.1 gof an oily material. Yield: 100%

The IR and MS data are as follows:

IR(neat)cm⁻¹ : 3360, 3280, 1600, 1585

MS(m/z): 161 (M⁺)

Step 3

Preparation of 2-[2-(4-chlorophenyl)sulfonylaminoethyl]indan:

The Step 2 of Reference Example 1 was followed and recrystallization wascarried out from a solvent mixture of ethyl acetate and isopropylether.Yield: 83%

The melting point, IR and MS data are as follows:

Melting point: 118°-121° C.

IR(KBr)cm⁻¹ : 3300, 1320, 1155

MS(m/z): 335 (M⁺)

The chemical formula is as follows: ##STR15##

Reference Example 4

Preparation of 2-[4-(4-chlorophenyl)sulfonylaminobutyl]indan:

The process of Reference Example 3 was followed starting4-(indan-2-yl)butanoic acid to obtain the title compound.

The melting point, IR and MS data are as follows:

Melting point: 77° C.

IR(KBr)cm⁻¹ : 3260, 1150

MS(m/z): 363 (M⁺)

The chemical formula is as follows: ##STR16##

EXAMPLE 1

Preparation of [2-(phenylsulfonylaminomethyl)indan-5-yl]acetic acid:

The aforementioned process D was followed to obtain the title compoundvia Steps 1 to 4.

Step 1

Preparation of [5-(ethoxycarbonylmethyl)indan-2-yl]acetic acid:

17.6 g (0.10 mol) of(indan-2-yl)acetic acid and 16.9 g (0.10 mol) ofethyl-alpha-chloro-alpha-(methylthio)acetate were dissolved in 100 ml ofdichloroethane, to which 17.6 ml (0.15 mol) of stannic chloride wasadded dropwise under ice-cooling. The mixture was stirred for 40 minutesat room temperature, the reaction mixture was poured into ice-water, andthe organic phase was washed with water, dried and condensed. Theresidue was dissolved in 250 ml acetic acid, and added with 70 g of zincpowder and heated at 110° C. for 1 hour. After cooling, the solid matterwas separated by filtration, and the filtrate was condensed underreduced pressure. The residue was added with 500 ml of chloroform,washed with water and dried. The solvent was then distilled off underreduced pressure to obtain 24.1 g of colorless solid. Yield: 92%

The melting point, IR and MS data are as follows:

Melting point: 56°-57° C.

IR(KBr)cm⁻¹ : 2990, 2910, 1725, 1680

MS(m/z): 262 (M⁺)

Step 2

Preparation ofEthyl[2-(benzyloxycarbonylaminomethyl)-indan-5-yl]acetate:

11.2 g (42.8 mmol) of [5-(ethoxycarbonylmethyl)indan-2-yl]acetic acidand 6.5 ml (46.7 mmol) triethylamine were dissolved in 140 ml toluene,to which was added 14.1 g (51.4 mmol) of diphenylphosphorylazide,followed by stirring for 30 minutes at room temperature. Subsequently,5.05 g (46.7 mmol) of benzyl alcohol was added and refluxed for 14hours. After cooling, the reaction mixture was washed with 1Nhydrochloric acid, water, 1N sodium hydroxide and water in this orderand dried. The solvent was distilled off and the residue was purified bysilica gel column chromatography (chloroform) to obtain 12.7 g colorlesssolid. Yield: 81%

The melting point, IR and MS data are as follows:

Melting point: 38°-41° C.

IR(KBr)cm⁻¹ : 1725, 1675

MS(m/z): 367 (M⁺)

Step 3

Preparation of ethyl[2-phenylsulfonylaminomethyl)indan-5-yl]acetate:

1.80 g (4.90 mmol) ofethyl[2-carbobenzyloxycarbonylaminomethyl)indan-5-yl]acetate wasdissolved in 30 ml of methanol, to which 500 mg of 10% palladium oncarbon was added and stirred for 2 hours in the stream of hydrogen. Thecatalyst was removed by filtration, the filtrate was condensed and theresidue was dissolved in 15 ml of ethyl acetate. 10 ml of water and 1.18g (8.51 mmol) of potassium carbonate was added thereto, and furtheradded dropwise 902 mg (5.11 mmol) of benzenesulfonylchloride. Afterstirring for 1 hour subsequent to the addition, the organic phase wascollected, dried and condensed under reduced pressure. The residue waspurified by silica gel column chromatography (chloroform) to obtain 1.78g of colorless oil. Yield: 97%

The IR and MS data are as follows:

IR(nujol)cm⁻¹ : 1725, 1615, 1580

MS(m/z): 373 (M⁺)

Step 4

Preparation of [2-(phenylsulfonylaminomethyl)indan-5-yl]acetic acid:

844 mg (2.26 mmol) ofethyl[2-(phenylsulfonylaminomethyl)-indan-5-yl]acetate was dissolved in3 ml of methanol, to which was added 5 ml of 1N sodium hydroxide andstirred for 1 hour at room temperature. Methanol was removed and theaqueous phase was washed with chloroform, and added with 1N hydrochloricacid for making the system acidic. The precipitates were extracted withethyl acetate, dried and condensed. The residue was recrystallized fromethyl acetate to obtain 679 mg crystals. Yield: 87%

The melting point, IR and MS data are as follows:

Melting point: 140°-141° C.

IR(KBr)cm⁻¹ : 3305, 2950, 1695

MS(m/z): 345 (M⁺)

The chemical formula is as follows: ##STR17##

EXAMPLES 2 to 22

The steps in Example 1 above were followed, and compounds having thefollowing nomenclature, chemical formulas, melting points, IR and MSdata were obtained.

The terms in the parentheses subsequent to the melting point dataindicate solvents from which the compounds were recrystallized.

EXAMPLE 2

[2-[(4-methylphenyl)sulfonylaminomethyl]indan-5-yl]acetic acid:##STR18## Melting point: 153-156° C. (Ethanol) IR(KBr)cm⁻¹ : 3250, 2930,1715

MS(m/z): 359 (M⁺)

EXAMPLE 3

[2-[(3,4-dimethoxyphenyl)sulfonylaminomethyl]indan-5-yl]acetic acid:##STR19## Melting point: 132°-133° C. (Ethanol) IR(KBr)cm⁻¹ : 3255,2930,

MS(m/z): 405 (M⁺)

EXAMPLE 4

[2-[(trans-2-styryl)sulfonylaminomethyl]indan-5-yl]acetic acid:##STR20## Melting point: 170°-172° C. (Ethanol) IR(KBr)cm⁻¹ : 3260,2930, 1695

MS(m/z): 371 (M⁺)

EXAMPLE 5

[2-(benzylsulfonylaminomethyl)indan-5-yl]acetic acid: ##STR21## Meltingpoint: 181°-182° C. (Ethanol) IR(KBr)cm⁻¹ : 3225, 2930,

MS(m/z): 359 (M⁺)

EXAMPLE 6

[2-(1-naphthylsulfonylaminomethyl)indan-5-yl]acetic acid: ##STR22##Melting point (decomposed): 58°-60° C. IR(KBr)cm⁻¹ : 3275, 2920, 1700

MS(m/z): 395 (M⁺)

EXAMPLE 7

[2-(2-naphthylsulfonylaminomethyl)indan-5-yl]acetic acid: ##STR23##Melting point: 180°-182° C. (Ethanol) IR (KBr) cm⁻¹ : 3230, 1925, 1690

MS(m/z): 395 (M⁺)

EXAMPLE 8

[2-(2-thienylsulfonylaminomethyl)indan-5-yl]acetic acid: ##STR24##Melting point: 110°-111° C. (aqueous methanol) IR(KBr)cm⁻ : 3250, 2920,1700

MS(m/z): 351 (M⁺)

EXAMPLE 9

[2-[(5-phenylsulfonyl-2-thienyl)sulfonylaminomethyl)indan-5-yl]aceticacid: ##STR25## Melting point: 164°-166° C. (Ethanol) IR(KBr)cm⁻¹ :3260, 2920, 1695

Ms(m/z): 491 (M⁺)

EXAMPLE 10

[2-[(4-trifluoromethyphenyl)sulfonylaminomethyl)indan-5-yl]acetic acid:##STR26## Melting point (decomposed): 183°-186° C. (Ethanol) IR(KBr)cm⁻¹: 3275, 2950, 1690, 1325, 1150

MS(m/z): 413 (M⁺)

EXAMPLE 11

[2-[(2,4-dichlorophenyl)sulfonylaminomethyl)indan-5-yl]acetic acid:##STR27## Melting point (decomposed): 153°-154° C. (Ethanol) IR(KBr)cm⁻¹: 3325, 2945, 1700, 1330, 1165

MS(m/z): 413 (M⁺)

EXAMPLE 12

2-[(4-methoxyphenyl)sulfonylaminomethyl)indan-5-yl]acetic acid:##STR28## Melting point (decomposed): 171-173° C. (Ethanol) IR(KBr)cm⁻¹: 3280, 2950, 1695, 1320, 1155

MS(m/z): 375 (M⁺)

EXAMPLE 13

[2-[(4-fluorophenyl)sulfonylaminomethyl)indan-5-yl]acetic acid:##STR29## Melting point: 180°-181° C. (aqueous ethanol) IR(KBr)cm⁻¹ :3300, 1700, 1155

MS(m/z): 363 (M⁺)

EXAMPLE 14

[2-[(4-bromophenyl)sulfonylaminomethyl)indan-5-yl]acetic acid: ##STR30##Melting point: 182°-183° C. (aqueous ethanol) IR(KBr)cm⁻¹ : 3295, 2940,1700, 1330, 1170

MS(m/z): 423(M⁺)

EXAMPLE 15

[2-[(3,4-dichlorophenyl)sulfonylaminomethyl)indan-5-yl]acetic acid:##STR31## Melting point: 174°-176° C. (aqueous ethanol) IR(KBr)cm⁻ :3250, 1695, 1325, 1160

MS(m/z): 415 (M⁺)

EXAMPLE 16

[2-[(4-ethylphenyl)sulfonylaminomethyl)indan-5-yl]acetic acid: ##STR32##Melting point: 140°-143° C. (Ethyl acetate-hexane) IR(KBr)cm⁻¹ : 3280,1700, 1155

MS(m/z): 373 (M⁺)

EXAMPLE 17

[2-[(4-t-butylphenyl)sulfonylaminomethyl)indan-5-yl]acetic acid:##STR33## Melting point: 187-189° C. (aqueous ethanol) IR(KBr)cm⁻¹ :3260, 1700, 1160

MS(m/z): 401 (M⁺)

EXAMPLE 18

[2-[(4-octylphenyl)sulfonylaminomethyl)indan-5-yl]acetic acid: ##STR34##Melting point: 136°-137 ° C. (aqueous ethanol) IR(KBr)cm⁻¹ : 3300, 2920,1700, 1330, 1155

MS(m/z): 457 (M⁺)

EXAMPLE 19

2-[(4-trifluoromethoxyphenyl)sulfonylaminomethyl)indan-5-yl]acetic acid:##STR35## Melting point: 185°-186° C. (aqueous ethanol) IR(KBr)cm⁻¹ :3300, 2940, 1700, 1155

MS(m/z): 429 (M⁺)

EXAMPLE 20

[2-[(4-butoxyphenyl)sulfonylaminomethyl)indan-5-yl]acetic acid:##STR36## Melting point 151°-152° C. (aqueous ethanol) IR(KBr)cm⁻¹ :3270, 1690

MS(m/z): 417 (M⁺)

EXAMPLE 21

2-[(4-cyanophenyl)sulfonylaminomethyl)indan-5-yl]acetic acid: ##STR37##Melting point: 198°-199° C. (aqueous ethanol) IR(KBr)cm⁻¹ : 3300, 2940,1700, 1335, 1160

MS(m/z): 370 (M⁺)

EXAMPLE 22

[2-[(4-nitrophenyl)sulfonylaminomethyl)indan-5-yl]acetic acid: ##STR38##Melting point: 148°-149° C. (aqueous ethanol) IR(KBr)cm⁻¹ : 3240, 1705,1350, 1155

MS(m/z): 390 (M⁺)

EXAMPLE 23

[2-[(4-aminophenyl)sulfonylaminomethyl)indan-5-yl]acetic acid: ##STR39##

1.95 g of [2-[(4-nitrophenyl)sulfonylaminomethyl)indan-5-yl]acetic acidobtained in Example 22 was dissolved in 50 ml of methanol and added with200 mg of 10% palladium on carbon, followed by stirring for 2 hours inthe stream of hydrogen gas. The catalyst was removed by filtration, thefiltrate was condensed and the residue was recrystallized from ethanolto obtain 1.43 g of crystals. Yield: 79%

Melting point: 201°-202° C.

IR(KBr)cm⁻¹ : 3470, 3380, 3280, 1695, 1150

MS(m/z): 360 (M⁺)

EXAMPLE 24

Preparation of [2-[(4-chlorophenyl)sulfonylaminomethyl)indan-5-yl]aceticacid:

The procedure of the aforementioned Process D was followed to obtain thetitle compound via the following Steps 1 to 3.

Step 1

Ethyl [2-[(4-chlorophenyl)sulfonylaminomethyl)indan-5-yl]acetate:

16.1 g (50.0 mmol) of [2-[(4-chlorophenyl)sulfonylaminomethyl)indan and9.27 g (55.0 mmol) of ethyl alpha-chloro-alpha-(methylthio)acetate weredissolved in 50 ml of methylene chloride, to which 6.44 ml (55.0 mmol)of stannic chloride was slowly added dropwise. After stirring for 3hours, the reaction mixture was poured into ice-water, and the organicphase was collected, washed, dried and condensed. The residue wasdissolved in 180 ml of acetic acid, added with 40 g of zinc powder andheated at 110° C. for 1 hour. After cooling, the precipitates werefiltrated and washed thoroughly with chloroform and the solvent wasremoved. The residue was dissolved in 300 ml of ethyl acetate, andwashed with water, saturated aqueous sodium bicarbonate solution andwater in this order, and dried. The solvent was distilled off underreduced pressure, and the residue was recrystallized from a solventmixture of ethyl acetate and hexane to obtain 16.7 g of colorlessneedles. Yield: 82%.

The melting point, IR and MS data are shown below:

Melting point: 94°-96° C.

IR(KBr)cm⁻¹ : 3230, 1730

MS(m/z): 379 (M⁺)

Step 2

Preparation of [2-[(4-chlorophenyl)sulfonylaminomethyl)indan-5-yl]aceticacid:

16.5 g of ethyl[2-[(4-chlorophenyl)sulfonylaminomethyl)indan-5-yl]acetate was suspendedin 50 ml of 1N sodium hydroxide, and heated at 80° C. for 1 hour. Aftercooling, conc. HCl was added thereto to make the system acidic. Theprecipitates were collected by filtration, followed by recrystallizationfrom 80% ethanol to obtain 14.0 g of colorless needles. Yield: 91%

The melting point, IR and MS data are shown below:

Melting point: 182°-186° C.

IR(KBr)cm⁻¹ : 3340, 1700

MS(m/z): 379 (M⁺) ##STR40##

Step 3

Preparation of sodium[2-[(4-chlorophenyl)sulfonylaminomethyl)indan-5-yl]acetate:

2.65 g (7.00 mmol) of[2-[(4-chlorophenyl)sulfonylaminomethyl]indan-5-yl]acetic acid obtainedabove was dissolved in 15 ml of 1N sodium hydroxide, and passed through100 ml of polystyrene gel (HP-20). Elution was carried out with 80%methanol, and the eluate was condensed to obtain colorless crystals,followed by recrystallization from 95% ethanol to obtain 2.39 g ofcolorless prisms. Yield: 85%

The melting point is as follows:

Melting point (decomposed): 133°-135° C.

The chemical formula is as follows:

EXAMPLES 25-28

The steps in Example 24 above were followed, and compounds having thefollowing nomenclature, chemical formulas, melting points, IR and MSdata were obtained.

EXAMPLE 25

[2-(2-phenylsulfonylaminoethyl)indan-5-yl]acetic acid: ##STR41## Meltingpoint: 102°-103° C. (Ethyl acetate--hexane) IR(nujol)cm⁻¹ : 3240, 1695

MS(m/z): 359 (M⁺)

EXAMPLE 26

[2-[2-(4-chlorophenyl)sulfonylaminoethyl]indan-5-yl]acetic acid:##STR42## Melting point: 146°-147° C. (Ethyl acetate--hexane)IR(nujol)cm⁻¹ : 3330, 1705

MS(m/z): 393 (M⁺)

EXAMPLE 27

[2-[3-(4-chlorophenyl)sulfonylaminopropyl]indan-5-yl]acetic acid:##STR43## Melting point: 163°-164° C. (aqueous ethanol) IR(KBr)cm⁻¹ :3260, 1690

MS(m/z): 407 (M⁺)

EXAMPLE 28

[2-[4-(4-chlorophenyl)sulfonylaminobutyl]indan-5-yl]acetic acid:##STR44## Melting point: 126° C. (aqueous ethanol) IR(KBr)cm⁻¹ : 3280,1700

MS(m/z): 421 (M⁺)

EXAMPLE 29

Preparation of 2-(phenylsulfonylaminomethyl)indan-5-hydroxyacetic acid:

The aforementioned Process B was followed to obtain the above compoundvia the following steps 1 to 8.

Step 1

Preparation of methyl(5-acetylindan-2-yl)acetate:

160 ml of methylene chloride was added with 52.9 g (0.388 mol) ofanhydrous aluminum chloride, and further added with 40 ml of methylenechloride containing 25.03 g (0.132 mol) of methyl(indan-2-yl)acetateunder ice-cooling. Subsequently, 13.1 ml (0.185 mol) of acetyl chloridewas added thereto dropwise. Stirring was conducted for 40 minutes at thesame temperature. The reaction mixture was poured into ice-water and theorganic phase was collected. After washing and drying, the solvent wascondensed under reduced pressure, and the residue was purified by silicagel column chromatography (ethyl acetate:hexane=1:2) to obtain 27.8 g ofan oily product. Yield: 91%

The IR and MS data are as follows:

IR(neat)cm⁻¹ : 1725, 1690

MS(m/z): 232 (M⁺)

Step 2

Methyl(5-acetoxyindan-2-yl)acetate:

11.0 g (47.0 mmol) of methyl(5-acetylindan-2-yl)acetate was dissolved in200 ml of methylene chloride, to which was added 14.6 g (67 mmol) ofm-chloroperbenzoic acid and stirred for 4 hours at room temperature,followed by refluxing for 17 hours. The reaction mixture was washed withsaturated aqueous sodium bicarbonate and water in this order, dried andthen the solvent was removed. The residue was purified by silica gelcolumn chromatography (chloroform) to obtain 11.3 g of an oily product.Yield: 97%

IR and MS data are as follows:

IR(neat)cm⁻¹ : 1750, 1730

MS(m/z): 248 (M⁺)

Step 3

Preparation of (5-benzyloxyindan-2-yl)acetic acid:

9.62 g (38.8 mmol) of methyl(5-acetoxyindan-2-yl)acetate was dissolvedin 150 ml of methanol, to which was added 1.17 g (8.5 mmol) of potassiumcarbonate and stirred for 1 hour at room temperature. The solvent wasdistilled off under reduced pressure, and the residue was dissolved in150 ml of acetone. 5.98 g (43.0 mmol) of potassium carbonate, 7.27 g(42.5 mmol) of benzylbromide were added thereto and refluxed for 5hours. After cooling, the precipitates were filtrated and condensedunder reduced pressure. The residue was dissolved in 100 ml of methanol,to which 12 ml of 20% sodium hydroxide were added and the mixture washeated at 50° C. for 1 hour. After cooling, methanol was removed, theresidue was made acidic with conc. HCl, and the precipitates wereextracted with chloroform. The organic phase was washed with water,dried and condensed under reduced pressure to obtain a pale brown solid.Recrystallization was carried out from a solvent mixture ofisopropylether and ethyl acetate to obtain 5.97 g of colorless crystals.Yield: 68%

The melting point and IR and MS data are as follows:

Melting point: 127°-129° C.

IR(neat)cm⁻¹ : 1695, 1615, 1485

MS(m/z): 282 (M⁺)

Step 4

Preparation of 5-benzyloxy-2-(t-butoxycarbonylaminomethyl)indan:

4.27 g (15.0 mmol) of (5-benzyloxy-2-yl)acetic acid was dissolved in 120ml of t-butanol, to which were added 1.96 (19.4 mmol) of triethylamineand 5.03 g (18.3 mmol) of diphenylphosphorylazide in this order, and themixture was refluxed for 27 hours. After cooling, the reaction mixturewas condensed under reduced pressure, the residue was dissolved in 200ml of ethyl acetate, followed by washing with 1N hydrochloric acid,water, 1N sodium hydroxide and water in this order, and then the solventwas removed. The residue was purified by silica gel columnchromatography (chloroform) and recrystallized from ethyl acetate andisopropylether to obtain 4.71 g of colorless crystals. Yield: 89%

The melting point, IR and MS data are as follows:

Melting point: 95-98° C.

IR(KBr)cm⁻¹ : 3350, 1670

MS(m/z): 353 (M⁺)

Step 5

Preparation of 2-(t-butoxycarbonylaminomethyl)-5-hydroxyindan:

3.53 g (10.0 mmol) of 5-benzyloxy-2-(t-butoxycarbonylaminomethyl)indanwas dissolved in 100 ml of methanol and added with 0.3 g of 10%palladium on carbon, followed by stirring for 4 hours in the stream ofhydrogen gas. The catalyst was removed by filtration, and the filtratewas condensed under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate: hexane=1:2) to obtain 2.79 gof a colorless oil. Yield: 94%

The IR and MS data are as follows:

IR(neat)cm⁻¹ : 3350, 1690

MS(m/z): 263 (M⁺)

Step 6

Preparation of ethyl[2-(t-butoxycarbonylaminomethyl)indan-5-oxy]acetate:

1.85 g (6.20 mmol) of 2-(t-butoxycarbonylaminomethyl)5-hydroxyindan wasdissolved in 20 ml of acetone, to which were added 1.52 g (11.0 mmol) ofpotassium carbonate and 1.10 g (6.60 mmol) of ethyl bromoacetate, andrefluxed for 3.5 hours. After cooling, the precipitates were filtrated,and the residue obtained by condensing the filtrate was purified bysilica gel column chromatography (ethyl acetate:hexane=1:2) to obtain1.90 g of colorless crystals. Yield: 80%

The melting point, IR and MS data are shown below:

Melting point: 56°-63° C.

IR(neat)cm⁻¹ : 1730, 1675

MS(m/z): 343 (M⁺)

Step 7

Preparation of ethyl[2-(phenylsulphonylaminomethyl)indan-5-oxy]acetate:

1.77 g (5.00 mmol) ofethyl[2-(t-butoxycarbonylaminomethyl)-indan-5-oxy]acetate was dissolvedin 6 ml of methylene chloride, to which was added 4 ml oftrifluoroacetic acid under ice-cooling and stirred for 1 hour. Thereaction mixture was diluted with 40 ml of methylene chloride. Asolution of 40 ml water containing 8.37 g (60 mmol) of potassiumcarbonate was added thereto and stirred vigorously. 10 minutes after,1.07 g (6.00 mmol) of phenylsulfonylchloride was added thereto, andstirred for further 1.5 hours. The organic phase was collected, driedand condensed, and the residue was purified by column gel chromatography(ethyl acetate:hexane=1:1) to obtain 1.68 g of a colorless oil. Yield:88%

The IR and MS data are shown below:

IR(nujol)cm⁻¹ : 3280, 1750, 1320, 1155

MS(m/z): 389 (M⁺)

Step 8

Preparation of 2-(phenylsulphonylaminomethyl)indan-5-hydroxy aceticacid:=

1.67 g (4.36 mmol) ofethyl[2-(phenylsulphonylaminomethyl)indan-5-oxy]acetate was dissolved ina mixture of 30 ml methanol and 6 ml of 1N sodium hydroxide, and stirredfor 1 hour at room temperature. Methanol was removed, the residue wasmade acidic by conc. HCl, and the precipitates were extracted withchloroform. After condensation, the solid matter was recrystallized fromacetic acid and isopropylether to obtain 1.33 g of colorless crystals.Yield: 86%

The melting point, IR and MS data are shown below:

Melting point: 150°-151° C.

IR(KBr)cm⁻¹ : 3270, 1745

MS(m/z): 361 (M⁺)

The chemical formula is as follows: ##STR45##

EXAMPLES 30-32

The steps in Example 29 above were followed, and compounds having thefollowing nomenclature, chemical formulas, melting points, IR and MSdata were obtained.

EXAMPLE 30

2-[(4-chlorophenyl)sulfonylaminomethyl)indan-5-hydroxyacetic acid:##STR46## Melting point (decomposed): 185°-188° C. (aqueous ethanol)IR(KBr)cm⁻¹ : 3240, 1720

MS(m/z): 395 (M⁺)

EXAMPLE 31

2-[(4-methoxyphenyl)sulfonylaminomethyl)indan-5-hydroxy acetic acid:##STR47## Melting point: 155°-156° C. (aqueous ethanol) IR(KBr)cm⁻¹ :3270, 1750, 1730, 1705

MS(m/z): 391 (M⁺)

EXAMPLE 32

2-[2-(4-chlorophenyl)sulfonylaminoethyl)indan-5-hydroxy acetic acid:##STR48## Melting point: 156°-158° C. (aqueous ethanol) IR(KBr)cm⁻¹ :3330, 1715

Ms(m/z): 409 (M⁺)

EXAMPLE 33

Preparation of[2-[(4-chlorophenyl)sulfonylaminomethyl]-indan-5-yl]carboxylic acid:

The aforementioned Process C was followed to obtain the title compoundvia the following Steps 1 to 2.

Step 1

Preparation of 5-acetyl-2-[(4-chlorophenyl)sulfonylaminomethyl]indan:

369 mg (1.15 mmol) of 2-[(4-chlorophenyl)sulfonylaminomethyl)indan wasdissolved in 5 ml of methylene chloride, to which were added 460 mg(4.20 mmol) of anhydrous aluminum chloride under ice-cooling and then302 mg (3.80 mmol) of acetyl chloride dropwise. After stirring for 30minutes at the same temperature, the reaction solution was admixed withice, and the organic phase was washed with water and saturated-aqueoussodium bicarbonate, dried and the solvent was removed. The residue wasrecrystallized from a solvent mixture of ethyl acetate andisopropylether to obtain 310 mg of colorless crystals. Yield: 75%

The melting point, IR and MS data are shown below:

Melting point: 102°-105° C.

IR(KBr)cm⁻ : 3250, 1675, 1320, 1150

MS(m/z): 363(M⁺)

Step 2

Preparation of[2-[(4-chlorophenyl)sulfonylaminomethyl]-indan-5-yl]carboxylic acid:

Under ice-salt cooling, 4.90 g (122 mmol) of sodium hydroxide wasdissolved in 50 ml of water, to which 1.6 ml (31.0 mmol) of bromine wasadded dropwise. This mixture was added to a solution of 100 ml of 90%dioxane containing 2.85 g (7.50 mmol) of5-acetyl-2-[(4-chlorophenyl)sulfonylaminomethyl]indan under cooling inan ice-salt bath. Thereafter, stirring was conducted for 1 hour duringwhich the temperature of the mixture was elevated to room temperature.The reaction solution was added with 10% sodium thiosulfate, and madeacidic with 1N HCl, followed by extracting with ethyl acetate. Thesolvent was removed, and the residue was recrystallized from acetic acidto obtain 2.36 g of colorless crystals. Yield: 86%

The melting point, IR and MS data are shown below:

Melting point (decomposed): 226°-228° C.

IR(KBr)cm⁻¹ : 3240, 1675

MS(m/z): 365 (M⁺)

The chemical formula is as follows: ##STR49##

EXAMPLES 34-36

The steps in Example 33 above were followed, and compounds having thefollowing nomenclature, chemical formulas, melting points, IR and MSdata were obtained.

EXAMPLE 34

[2-[2-(4-chlorophenyl)sulfonylaminoethyl)indan-5-yl]-carboxylic acid:##STR50## Melting point (decomposed): 210°-213° C. IR(KBr)cm⁻¹ : 3270,1685

MS(m/z): 379 (M⁺)

EXAMPLE 35

[2-[3-(4-chlorophenyl)sulfonylaminopropyl)indan-5-yl]carboxylic acid:##STR51## Melting point (decomposed): 183°-186° C. IR (KBr) cm⁻¹ : 3270,1670

MS(m/z): 393 (M⁺)

EXAMPLE 36

[2-[4-(4-chlorophenyl)sulfonylaminobutyl)indan-5-yl]carboxylic acid:##STR52## Melting point: 152°-154° C. IR(KBr)cm⁻¹ : 3280, 1685

MS(m/z): 407 (M⁺)

EXAMPLE 37

Preparation oftrans-3-[2-[(4-chlorophenyl)sulfonylaminomethyl)indan-5-yl]acrylic acid:

The aforementioned Process F was followed to obtain the title compoundvia the following Steps 1 to 3.

Step 1

Preparation of 5-formyl-2[(4-chlorophenyl)sulfonylaminomethyl]indan:

5.33 g (40.0 mmol) of anhydrous aluminum chloride was suspended in 20 mlof methylenechloride and added with 1.61 g (5.00 mmol) of2-[(4-chlorophenyl)sulfonylaminomethyl]indan, followed by cooling at-20° C. 10 ml of methylene chloride containing as dissolved 0.68 ml (7.5mmol) of dichloromethylmethylether was slowly added dropwise thereto,followed by stirring for 1 hour at the same temperature. The reactionsolution was poured into ice-water and stirred for 1 hour. Thereafter,the organic phase was collected, washed, dried, and the solvent wasremoved. The residue was purified by silica gel column chromatography(chloroform), followed by recrystallizing from a solvent mixture ofethylacetate and hexane to obtain 375 mg of colorless crystals. Yield:22%

The melting point, IR and MS data are shown below:

Melting point: 80°-82° C.

IR(KBr)cm⁻¹ : 3240, 1685

MS(m/z): 349 (M⁺)

Step 2

Preparation ofethyl-trans-3-[2-[(4chlorophenyl)sulfonylaminomethyl]indan-5-yl]acrylate:

To 20 ml of methylene chloride, 1.29 g (3.68 mmol) of5-formyl-2-[(4-chlorophenyl)sulfonylaminomethyl]indan and 1.28 g (3.68mmol) of carboethoxymethylene triphenylphosphoran were added and stirredfor 16 hours at room temperature. The reaction solution was purified bysilica gel column chromatography.(chloroform), and the precipitatesobtained were recrystallized from a solvent mixture of ethyl acetate andhexane. 1.18 g of colorless crystals were obtained. Yield: 77%

The melting point, IR and MS-data are as follows:

Melting point: 113°-115° C.

IR(KBr)cm⁻¹ : 3230, 1705, 1630

MS(m/z): 387 (M⁺)

Step 3

Preparation oftrans-3-[2-[(4-chlorophenyl)sulfonylaminomethyl]indan-5-yl]acrylic acid:

465 mg (1.20 mmol)ofethyl-trans-3-[2-[(4-chlorophenyl)sulfonyl-aminoethyl]indan-5-yl]acrylatewas suspended in 5 ml of sodium hydroxide and stirred for 5 hours atroom temperature. 2N hydrochloric acid was added thereto for making thesystem acidic, and the precipitated crystals were extracted withmethylene chloride. After dried, the solvent was removed, and theresidue was recrystallized from ethanol to obtain 405 mg of colorlesscrystals. Yield: 86%

The melting point, IR and MS data are as follows:

Melting point: 240°-241° C.

IR(KBr)cm⁻¹ : 3260, 1685, 1630

MS(m/z): 359 (M⁺)

The chemical formula is as follows: ##STR53##

EXAMPLE 38

Preparation of3-[2-[(4-chlorophenyl)sulfonylaminomethyl]indan-5-yl]propionic acid:

The aforementioned Process F was followed to obtain the title compoundvia the following Steps 1 to 2.

Step 1

Preparation ofethyl-3-[2-[(4-chlorophenyl)sulfonylaminomethyl]indan-5-yl]propionate:

387 mg (1.00 mmol) ofethyl-trans-3-[2-[(4chlorophenyl)sulfonylaminomethyl]indan-5-yl]acrylatewas dissolved in 10 ml of ethanol, to which was added 24 mg (0.1 mmol)ofnickel chloride·6H₂ O. Under ice-cooling, to this solution was added 76mg (2.00 mmol) of sodium borohydride, followed by stirring at roomtemperature overnight. The ethanol was distilled off, the residue wasadded with 10 ml of water, and the obtained product was extracted withethyl acetate, followed by washing and drying then condensing. Theobtained crystals were recrystallized from a solvent mixture of hexaneand ether to obtain 241 mg colorless crystals. Yield: 62%

The melting point, IR and MS data are as follows:

Melting point: 90°-93° C.

IR(KBr)cm⁻¹ : 3260, 1725, 1585, 1320, 1155

MS(m/z): 389 (M⁺)

Step 2

Preparation of3-[2-[(4-chlorophenyl)sulfonylaminomethyl]indan-5-yl]propionic acid:

195 mg (0.50 mmol) ofethyl-3-[2-[(4chlorophenyl)sulfonylaminomethyl]indan-5-yl]propionate wassuspended in 3 ml of 2N sodium hydroxide and heated at 70° C. for 2hours. After cooling, the system was made acidic with conc. HCl in anice bath. The precipitated crystals were collected, recrystallized froma solvent mixture of ethyl acetate and hexane to obtain 137 mg ofcolorless flakes. Yield: 76%

The melting point, IR and MS data are as follows:

Melting point: 189°-191° C.

IR(KBr)cm⁻¹ : 3270, 1695, 1595, 1320, 1160

MS(m/z): 361 (M⁺)

The chemical formula is as follows: ##STR54##

EXAMPLE 39

The steps in Example 38 above were followed, and compounds having thefollowing nomenclature, chemical formulas, melting points, IR and MSdata were obtained. Yield: 66%

3-[2-[(4-methoxyphenyl)sulfonylaminomethyl)indan-5-yl]propionic acid:##STR55## Melting point:. 147°-151° C. (aqueous ethanol) IR(KBr)cm⁻¹ :3260, 1695, 1155

MS(m/z): 389 (M⁺)

EXAMPLE 40

Preparation of4-[2-[(4-chlorophenyl)sulfonylaminomethyl]indan-5-yl-4-oxobutanoic acid:

The aforementioned Process E was followed to obtain the title compoundvia the following Step.

6.82 g (51.2 mmol) of anhydrous aluminum chloride was suspended in 35 mlof dichloroethane, to which was added 4.26 g (13.3 mmol) of2-[(4-chlorophenyl)sulfonylaminomethyl]indan prepared in ReferenceExample 1. 2.07 g (20.6 mmol) of succinic anhydride was addedportionwise to the mixture under ice-cooling. Thereafter, stirring wascarried out for 1.5 hours at room temperature, the reaction solution waspoured into ice-water, and then the precipitated crystals werefiltrated, washed, and recrystallized to obtain 4.75 g of colorlesscrystals. Yield: 85%

The melting point, IR and MS data are as follows:

Melting point (decomposed): 192°-194° C.

IR(KBr)cm⁻¹ : 3250, 1690, 1675

MS(m/z): 421 (M⁺)

The chemical formula is as follows: ##STR56##

EXAMPLES 41-44:

The procedure in Example 40 above was followed, and compounds having thefollowing nomenclature, chemical formulas, melting points, IR and MSdata were obtained.

EXAMPLE 41

4-[2-[2-(4-chlorophenyl)sulfonylaminoethyl)indan-5-yl]-4-oxobutanoicacid: ##STR57## Melting point: 144°-146° C. (acetic aid) IR(KBr)cm⁻¹ :3300, 1715, 1675

MS(m/z): 435 (M⁺)

EXAMPLE 42

4-[2-[(4-methoxyphenyl)sulfonylaminomethyl)indan-5-yl]-4-oxobutanoicacid: ##STR58## Melting point: 150°-151° C. (aqueous ethanol)IR(KBr)cm⁻¹ : 3260, 1695,

MS(m/z): 417 (M⁺)

EXAMPLE 43

5-[2-[(4-chlorophenyl)sulfonylaminomethyl)indan-5-yl]-4-oxopentanoicacid: ##STR59## Melting point: 159°-161° C. (Ethanol) IR(KBr)cm⁻¹ :3260, 1690, 1680, 1155

MS(m/z): 435 (M⁺)

EXAMPLE 44

6-[2-[(4-chlorophenyl)sulfonylaminomethyl)indan-5-yl]-6-oxohexanoicacid: ##STR60## Melting point: 154°-155° C. (aqueous alcohol)IR(KBr)cm⁻¹ : 3260, 1680, 1430, 1325, 1155

Ms(m/z): 449 (M⁺)

EXAMPLE 45

Preparation of6-[2-[(4-chlorophenyl)sulfonylaminoethyl)indan-5-yl]-3-oxo-2,3,4,5-tetrahydropyridazine:

The title compound was obtained by the following procedure.

1.730 g of4-[2-[(4-chlorophenyl)sulfonylaminomethyl]indan-5-yl-4-oxobutanoic acidobtained in Example 40 was suspended in acetic acid (12 ml), and addedwith hydrazine·H₂ O (332 mg) then refluxed. After 3.5 hours, acetic acidwas distilled off under reduced pressure, and the obtained residue wasadded with saturated aqueous sodium bicarbonate. The crystals producedwere collected by filtration. The crystals were recrystallized fromacetic acid to obtain 1.331 g of colorless crystals. Yield: 78%

The melting point, IR and MS data are shown below.

Melting point: 193°-194° C.

IR(KBr)cm⁻¹ : 3250, 1685, 1315, 1150

MS(m/z): 417 (M⁺)

The chemical formula is as follows: ##STR61##

EXAMPLE 46

Preparation of5-[2-[(4-chlorophenyl)sulfonylaminomethyl]indan-5-yl]-3-oxo-2,3,4-trihydropirazole:

The title compound was obtained via the following steps 1 to 2.

Step 1

Preparation of ethyl3-[2-[(4chlorophenyl)sulfonylaminomethyl]indan-5-yl]-3-oxopropionate:

The title compound was obtained in a similar procedure to Example 40.Yield: 70%

The melting point, IR and MS data are shown below.

Melting point: 78°-79° C. (Ethyl acetate--isopropyl alcohol)

IR(KBr)cm⁻¹ : 3240, 2920, 1730, 1675, 1150

MS(m/z): 435 (M⁺)

Step 2

Preparation of5-[2-[(4-chlorophenyl)sulfonylaminomethyl]indan-5-yl]-3-oxo-2,3,4-trihydropyrazole:

The title compound was obtained in a similar procedure to Example 45.Yield: 72%

The melting point, IR and MS data are shown below.

Melting point: 274°-275° C. (Acetic acid)

IR(KBr)cm⁻¹ : 3250, 1700, 1600, 1150

MS(m/z): 403 (M⁺)

The chemical formula is as follows: ##STR62##

EXAMPLE 47

Preparation of3-[2-[(4-chlorophenyl)sulfonylaminomethyl]indan-5-yl]-3-hydroxypropionicacid:

The title compound was obtained via the following steps 1 and 2.

Step 1

Preparation of ethyl3-[2-[(4-chlorophenyl)sulfonylaminomethyl]indan-5-yl]-3-hydroxypropionate:

4.46 g of ethyl3-[2-[(4-chlorophenyl)sulfonylaminomethyl]indan-5-yl]-3-oxopropionateobtained in Step 1 of Example 46 was dissolved in 60 ml of ethanol, towhich 193 mg of sodium borohydride was added under ice-cooling, followedby stirring for 2 hours at the same temperature. Subsequently, thesolvent was distilled off under reduced pressure. The residue was addedwith ethyl acetate, washed with water and dried. The solvent was removedunder reduced pressure. The residue was recrystallized from a solventmixture of ethyl acetate and isopropyl ether to obtain 4.37 g ofcolorless crystals. Yield: 99%

The melting point, IR and MS data are as follows:

Melting point: 108°-111° C.

IR(KBr)cm⁻¹ : 3260, 1725, 1325, 1155

MS(m/z): 437 (M⁺)

Step 2

Preparation of ethyl3-[2-[(4-chlorophenyl)sulfonylaminomethyl]indan-5-yl]-3-hydroxypropionicacid:

The title compound was obtained by following the procedure similar toStep 4 in Example 1. Yield: 89%

The melting point, IR and MS data are as follows:

Melting point: 173°-174° C. (Ethyl acetate)

IR(KBr)cm⁻¹ : 3260, 1705, 1325, 1155

MS(m/z): 409 (M⁺)

The chemical formula is as follows: ##STR63##

EXAMPLE 48

Preparation of4-[2-[(4-chlorophenyl)sulfonylaminomethyl]indan-5-yl]butanoic acid:

The title compound was obtained via the following steps 1 and 2.

Step 1

Preparation of ethyl4-[2-[(4-chlorophenyl)sulfonylaminomethyl]indan-5-yl]-4-oxobutylate:

The title compound was obtained by following the procedure similar toExample 40. Yield 84%

The melting point, IR and MS data are as follows:

Melting point: 86°-87° C. (Ethyl acetate--isopropyl ether)

IR(KBr)cm⁻¹ : 3240, 1725, 1665, 1160

MS(m/z): 449 (M⁺)

Step 2

Preparation of ethyl4-[2-[(4-chlorophenyl)sulfonylaminomethyl]indan-5-yl]butylate:

6.75 g of ethyl4-[2-[(4-chlorophenyl)sulfonylaminomethyl]indan-5-yl]-4-oxobutylate wasdissolved in 10 ml of trifluoroacetic acid, to which 5.4 ml oftriethylsilane was added and stirred overnight at room temperature. Thereaction solution was added with water, then the product was extractedwith ethyl acetate, followed by washing with water, saturated aqueoussodium bicarbonate and saturated saline in this order, drying anddistilling off the solvent under reduce pressure. The obtained crystalswere recrystallized from a solvent mixture of ethyl acetate and hexane.5.83 g of colorless crystals were obtained. Yield: 89%

The melting point, IR and MS data are as follows:

Melting point: 70°-71° C.

IR(KBr)cm⁻¹ : 3260, 1735, 1155

MS(m/z): 435(M⁺)

The chemical formula is as follows: ##STR64##

EXAMPLES 49-52

The steps in Example 24 above were followed, and compounds having thefollowing nomenclature, chemical formulas, melting points, IR and MSdata were obtained.

EXAMPLE 49

5-[2-[(4-chlorophenyl)sulfonylaminomethyl)indan-5-yl]pentanoic acid:##STR65## Melting point: 164°-165° C. (Ethanol) IR(KBr)cm⁻¹ : 3260,1700, 1155

MS(m/z): 421 (M⁺)

EXAMPLE 50

4-[2-[(4-methoxyphenyl)sulfonylaminomethyl)indan-5-yl]butanoic acid:##STR66## Melting point: 114°-115° C. (aqueous ethanol) IR(KBr)cm⁻¹ :3300, 1700,

MS(m/z): 403 (M⁺)

EXAMPLE 51

6-[2-[(4-chlorophenyl)sulfonylaminomethyl)indan-5-yl]hexanoic acid:##STR67## Melting point: 152°-153° C. (aqueous ethanol) IR(KBr)cm⁻¹ :3250, 1700, 1435, 1325, 1155

MS(m/z): 435 (M⁺)

EXAMPLE 52

4-[2-(2-naphthylsulfonylaminomethyl)indan-5-yl]butanoic acid: ##STR68##Melting point: 165°-670° C. (aqueous ethanol) IR(KBr)cm⁻¹ : 3255, 1695,1155

MS(m/z): 423 (M⁺)

EXAMPLE 53

Formulation of Preparation Example 1:

    ______________________________________                                        Compound of Example 1                                                                             20 g                                                      Lactose            315 g                                                      Corn starch        125 g                                                      Crystalline cellulose                                                                             25 g                                                      ______________________________________                                    

The ingredients indicated above were blended to form a uniform mixture,to which 200 ml of 7.5% aqueous hydroxypropylcellulose solution wasadded, and then the obtained mixture was granulated with an extruderequipped with a screen of 0.5 mm in diameter. Immediately thereafter,the granules were rounded with a marumerizer and dried to obtain agranule preparation.

EXAMPLE 54

Formulation of Preparation Example 2:

    ______________________________________                                        Compound of Example 24                                                                              20 g                                                    Lactose               100 g                                                   Corn starch           36 g                                                    Crystalline cellulose 30 g                                                    Carboxymethylcellulose calcium                                                                      10 g                                                    Magnesium stearate     4 g                                                    ______________________________________                                    

The ingredients indicated above were blended to form a uniform mixture,and prepared into tablets each weighing 200 mg with a single-punchtableting machine equipped with a die of 7.5 mm in diameter.

EXAMPLE 55

Formulation of Preparation Example 3:

    ______________________________________                                        Compound of Example 40                                                                             40 g                                                     Lactose             232 g                                                     Corn starch         108 g                                                     Polyvinyl pyrrolidone                                                                              20 g                                                     ______________________________________                                    

The ingredients indicated above were blended to form a uniform mixture,to which 180 ml of 70%(v/v) isopropyl alcohol was added, and formed intogranules with an extruder equipped with a screen of 0.8 mm in diameter.Immediately thereafters, the obtained granules were rounded with amarumerizer and dried. The granules were placed in No. 2 hard gelatincapsule to prepare a capsule preparation, each content weighing 240 mg.

TEST EXAMPLES

Test 1

Inhibitory effect on U46619 induced contraction in rat aorta:

The thoracic aorta of a SD male rat (Charles River Co., Ltd.) wasremoved and prepared a rectangular sample which had a long side runningin the parallel direction of the circular muscle. The sample was kept at37° C., bubbled with 95% oxygen gas containing 5% CO₂, and suspended ina 10 ml organ bath filled with a Krebs-Henseleit solution at 2 g restingtension. 10⁻⁷ M of U46619 which is a stable active substance of TXA₂ wasadded portionwise. After the contraction responses were stabilized, thetest compound was added to the organ bath, and its antagonism wasevaluated. A concentration-relaxation curve was obtained, to which wasapplied a logit method to obtain pIC₅₀ values. The results are shown inTable 1.

                  TABLE 1                                                         ______________________________________                                        Test Compounds      pIC.sub.50                                                ______________________________________                                        Compound of Example 1                                                                             7.89                                                      Compound of Example 24                                                                            8.52                                                      Compound of Example 25                                                                            6.50                                                      Compound of Example 29                                                                            7.50                                                      Control compound*   6.37                                                      ______________________________________                                         *4-(2-phenylsulfonylaminoethyl)phenoxy acetic acid                       

From the data in Table 1, it is understood that any of those which wereadded with compounds of the present invention show excellentantagonistic action.

Test 2

Human platelet aggregation inhibitory action (in vitro):

Blood samples were collected from healthy humans. 9 parts by volume ofthe collected blood was mixed with 1 part by volume of an aqueous3.8%(W/v) trisodium citrate, and the mixture was subjected tocentrifugal separation for collecting the supernatant-to prepare aplatelet rich plasma (PRP). A further centrifugation was-performed toseparate a platelet poor plasma (PPP). PRP was diluted with PPP toadjust the number of platelets to approximately 4×10⁵ cells/ml.Subsequently, 200 micro liters of PRP were added with the blood sampleand 25 micro liters of an equimolar aqueous sodium hydrogencarbonatesolution, and stirred for 2 minutes at 37° C. Thereafter, U46619 wasadded thereto for inducing platelet aggregation. The plateletaggregation was measured in accordance with a Born's method ("Nature",vol 194, page 927 (1962)), and inhibition against the plateletaggregation was examined. The platelet aggregation inhibitory action ofthe test compounds was expressed as the IC₅₀ value (concentrationrequired for inhibiting the platelet aggregation induced by 1 μM ofU46619 by 50%). The data are shown in Table 2.

                  TABLE 2                                                         ______________________________________                                        Test compounds     IC.sub.50 (μM)                                          ______________________________________                                        Compound of Example 1                                                                            0.72                                                       Compound of Example 24                                                                           0.77                                                       Compound of Example 25                                                                           2.45                                                       Compound of Example 30                                                                           0.31                                                       Compound of Example 33                                                                           0.85                                                       Compound of Example 34                                                                           0.60                                                       Compound of Example 40                                                                           1.12                                                       Control compound*  2.53                                                       ______________________________________                                         *4-(2-phenylsulfonylaminoethyl)phenoxy acetic acid                       

From the data in Table 2, it is understood that the compounds accordingto the present invention show excellent platelet aggregation inhibitoryaction.

Test 3

Toxicity Test: Groups of 4-5 week old ICR mice (Charles River Co.,Ltd.), each group consisting of 10 mice, were provided for the test. Thecompounds obtained in aforementioned Examples were respectivelysuspended in 10% gum arabic and each was orally administered to the ratsin a dosage of 300 mg/kg. The rats were observed for 7 days. No deathwas found under the above conditions.

INDUSTRIAL APPLICABILITY

Since the present compounds have excellent TXA₂ antagonism and are verysafe, they have a wide utility in the medical field such as in thetreatment and prevention of various diseases caused by TXA₂, such asembolism and thrombosis, including cerebral thrombosis, coronarythrombosis, pulmonary embolism, chronic arterial obstruction,thromboangiitis, and also in the treatment, alleviation and preventionof myocardial ischemia, angina pectoris, coronary contraction,cerebrovascular contraction after subarachnoidal hemorrhage, cerebralhemorrhage, asthma, and the like.

We claim:
 1. An indan derivative represented by the formula (1) or apharmaceutically acceptable salt thereof: ##STR69## wherein R¹represents an alkyl having 1-12 carbon atoms, benzyl, styryl, naphthyl,optionally substituted phenyl or optionally substituted thienyl; R²represents carboxyl, or alkoxycarbonyl, wherein the alkoxy moiety has1-4 carbon atoms;Y represents --(CH₂)_(p) -- (wherein p represents aninteger of 0 to 5), --CO--(CH₂)_(q) ˜, --CH(OH)--(CH₂)_(q) ˜, (wherein qrepresents an integer of 1 to 4, and the symbol ˜ represents a linkageto R²), oxymethylene or ethylene; and n represents an integer of 1 to 4.2. A thromboxane antagonist composition containing, as its activeingredient, an indan derivative represented by the formula (1) or apharmaceutically acceptable salt thereof: ##STR70## wherein R¹represents an alkyl having 1-12 carbon atom, benzyl, styryl, naphthyl,optionally substituted phenyl or optionally substituted thienyl; R²represents carboxyl, or alkoxycarbonyl, wherein the alkoxy moiety has1-4 carbon atoms;Y represents --(CH₂)_(p) -- (wherein p represents aninteger of 0 to 5), --CO--(CH₂)_(q) ˜, --CH(OH)--(CH₂)_(q) ˜, (wherein qrepresents an integer of 1 to 4, and the symbol ˜ represents a linkageto R₂), oxymethylene or ethylene; and n represents an integer of 1 to 4.3. 2-[(4-Chlorophenyl)sulfonyl-aminomethyl)indan-5-yl]acetic acid.
 4. Athromboxane antagonist composition containing, as its active ingredient,the compound of claim
 3. 5. A method for the treatment of thrombosis,cerebral thrombosis, coronary thrombosis, pulmonary embolism, chronicarterial obstruction, thromboangitis, myocardial ischemia, anginapectoris, coronary contraction, cerebrovascular contraction aftersubarachnoidal hemorrhage, cerebral hemorrhage and asthma, comprisingadministering to an animal or human subject the thromboxane antagonistcomposition of claim
 2. 6. A method for the treatment of thrombosis,cerebral thrombosis, coronary thrombosis, pulmonary embolism, chronicarterial obstruction, thromboangitis, myocardial ischemia, anginapectoris, coronary contraction, cerebrovascular contraction aftersubarachnoidal hemorrhage, cerebral hemorrhage and asthma, comprisingadministering to an animal or human subject the thromboxane antagonistcomposition of claim 4.